摘要
目的：研究母爱剥夺应激及慢性不可预知性应激对大鼠行为及其多巴胺能中脑皮质边缘神经通路内多巴胺受体、转运体及脑源性营养因子的影响,了解不同慢性应激范式是否可诱发不同抑郁表型,并探讨不同抑郁表型发生的多巴胺能中脑皮质边缘神经通路机制。
方法：将新生SD大鼠按窝别随机分入母爱剥夺应激组(MD),n=8)、慢性不可预知性应激组(CUPS, n=8)及对照组(C,n=8)。MD组大鼠在出生后接受母爱剥夺应激,CUPS组大鼠10周龄起接受慢性不可预知性应激,C组大鼠不接受任何实验性处理。所有大鼠在13周龄时接受包括旷场实验、强迫游泳实验及糖水偏爱实验的行为学评估,分别记录大鼠在旷场实验中的爬行总路程、直立次数、中央格比例及大便颗数,在强迫游泳实验中的静止漂浮时间以及在糖水偏爱实验中的糖水偏爱率。于行为学评估结束后处死大鼠,收集其中脑腹侧被盖区(VTA)、前额叶皮质、伏隔核、杏仁核、嗅球及纹状体,采用实时定量荧光PCR技术及免疫印迹技术检测三组大鼠上述脑区内多巴胺受体(包括D1样受体：DRD1、DRD5及D2样受体：DRD2、DRD3、DRD4)、转运体(DAT)及脑源性营养因子(BDNF)的mRNA及蛋白水平。采用单因素方差分析或Kruskal-wallis H检验及皮尔逊相关分析对数据进行统计分析。
结果：
1.行为学结果：(1)旷场实验：三组爬行总路程无差异；MD组与CUPS组的直立次数、大便颗数无差异,但均少于C组；MD组与C组的中央格比例无差异,但均高于CUPS组；(2)强迫游泳实验：CUPS组的静止漂浮时间长于MD组,且两者均长于C组：(3)糖水偏爱实验：MD组的糖水偏爱率低于CUPS组,且两者均低于C组。
2.蛋白检测结果：(1)VTA：与C组比,MD组D1、D2样受体、DAT及BDNF蛋白水平降低,CUPS组DRD2增高,DRD5、DRD4降低；与CUPS组比,MD组D1样受体、DRD2、DRD3及BDNF降低。(2)前额叶皮质：与C组比,MD组D1样受体、DRD3、DRD4及DAT蛋白水平增高,BDNF降低,CUPS组的D1样受体、DAT增高,DRD2、BDNF降低：与CUPS组比,MD组DRD3、DRD4增高,DRD5、DAT降低。(3)伏隔核：与C组比,MD组D1、D2样受体及DAT的蛋白水平增高,BDNF降低,CUPS组D1、D2样受体及DAT增高；与CUPS组比,MD组DAT增高,BDNF降低。(4)杏仁核：与C组比,MD组D1、D2样受体的蛋白水平增高,CUPS组DRD5、D2样受体及DAT增高；与CUPS组比,MD组DRD1增高,DRD4、DAT降低。(5)嗅球：与C组比,MD组D1、D2样受体及DAT的蛋白水平增高,CUPS组DRD1、DRD2增高。(6)纹状体：与C组比,MD组DRD5、D2样受体及DAT的蛋白水平增高,DRDl降低,CUPS组DRD5、DRD2、DRD3、DAT及BDNF增高,DRD1降低。
3. mRNA检测结果：除下列指标外,其余指标组间比较同蛋白水平检测结果。MD组VTA内DRD1高于C组,MD组及CUPS组前额叶皮质及伏隔核内BDNF均高于C组；
4.行为学与生物学指标的相关分析结果：(1)大鼠旷场试验中的直立次数与其VTA内DRD5、DRD3、DRD4及其纹状体DRD1的蛋白水平呈正相关,与其纹状体内D2样受体、DAT及前额叶皮质内DRD5、DAT的蛋白水平呈负相关；(2)大鼠强迫游泳实验中的静止漂浮时间与其杏仁核内D2样受体、DAT及前额叶皮质内DRD1、DRD5、DAT的蛋白水平呈正相关；(3)大鼠糖水偏爱实验中的糖水偏爱率与其VTA内DRD5、DRD3、DAT的蛋白水平呈正相关,与其伏隔核内D2样受体、DAT及嗅球内D1、D2样受体、DAT的蛋白水平呈负相关。
结论：
1.不同慢性应激可诱发大鼠不同抑郁表型。
2.不同慢性应激对大鼠多巴胺能中脑皮质边缘神经通路内D1、D2样多巴胺受体及DAT基因表达的影响不同。
3.不同抑郁样行为涉及不同的多巴胺能神经通路异常机制。
4.不同慢性应激对大鼠多巴胺能中脑皮质边缘神经通路内各脑区神经可塑性的影响不同。
Objective:To study the effect of maternal deprivation and chronic unpredictable stress on the behaviors and the expression of dopamine receptors gene, dopamine transporter gene and brain-derived neurotrophic factor gene in the mesolimbocortical dopaminergic neural pathway of rats; To explore whether depressive phenotypes induced by the two stress paradigms differ from each other or not and determine the certain anomaly in the mesolimbocortical dopaminergic neural pathway involved.
Methods:Newborn rats were randomly divided into three groups, maternal deprivation group (MD, n=8), chronic unpredictable stress group (CUPS, n=8) and control group (C, n=8). MD rats were exposed to maternal deprivation from postnatal day1to14; CUPS rats were exposed to chronic unpredictable stress for3weeks at the age of10weeks; Control rats received no experimental handle but standard husbandry care. Assessment of rats'depressive behaviors was conducted when they are13weeks old via open field test, forced swimming test and sucrose preference test, four indices including the total distance rats crawled, the rate of central area, vertical activity and the number of fecal pallets were recorded during open field test, the floating time was measured during the forced swimming test and the sucrose and water intake was recorded during sucrose preference test to evaluate the exploratory interest,anxiety level,desperation behavior and anhedonia of rats respectively. All the rats were rapidly decapitated after behavioral tests, and the ventral tegmental area, prefrontal cortex, nucleus accumbens,amygdala, olfactory bulb and striatum were rapidly collected. The protein and mRNA level of dopamine receptors including DRD1/DRD5/DRD2/DRD3/DRD4, dopamine transporter(DAT) and brain-derived neurotrophic factor(BDNF) in the brain regions mention above were detected by Western Blot and Real-Time PCR respectively. One-way analysis of variance (ANOVA) and LSD-test or Kruskal-wallis H and Nemenyi-test and Pearson correlation test was used for analyzing the data collected from the study.
Results:
1.The result of behavior tests:(1) the result of open field tests:1) total distance rats crawled:no difference in the total distance rats crawled in the open field arena was found between three groups (p>0.05);2) vertical activity:the MD and CUPS rats exhibited no difference in vertical activity, and both of which decreased compared to control rats(p<0.05);3) central area rate:the MD and control rats exhibited no difference in central area rate, and both of which increased compared to CUPS rats(p<0.05);4) the number of fecal pallets:the MD and control rats exhibited no difference in the number of fecal pallets excreted during the open field test, and both of which decreased compared to CUPS rats(p<0.05).(2) the forced swimming test:CUPS rats shown longer floating time in the forced swimming test than MD rats did(P<0.05), the floating time of which were longer than that of the control rats(p<0.05).(3) sucrose preference test:the sucrose preference rate of MD rats was lower than that of CUPS rats(p<0.05), and both of them were lower than the control rats(p<0.05).
2. The result of protein detection:(1) in ventral tegmental area(VTA): compared to control rats, protein level of DRD1, DRD5, DRD2, DRD3, DRD4,DAT and BDNF were downregulated in VTA of MD rats(p<0.05), DRD2was upregulated and DRD5,DRD4were downregulated in VTA of CUPS rats(p<0.05); compared to CUPS rats, protein level of DRD1, DRD5, DRD2, DRD3and BDNF were downregulated in VTA of MD rats(p<0.05).(2) in prefrontal cortex(PFC):compared to control rats, protein level of DRD1, DRD5, DRD3, DRD4and DAT were upregulated and BDNF protein level was downregulated in PFC of MD rats(p<0.05), DRD1, DRD5and DAT were upregulated and DRD2, BDNF were downregulated in PFC of CUPS rats(p<0.05); compared to CUPS rats, DRD3,DRD4were upregulated and DRD5,DAT were downregulated in PFC of MD rats(p<0.05).(3) in nucleus accumbens(NAc):compared to control rats, DRD1, DRD5, DRD2, DRD3, DRD4and DAT protein level were upregulated and BDNF was downregulated in NAc of MD rats(p<0.05), DRD1, DRD5, DRD2, DRD3, DRD4and DAT were upregulated in NAc of CUPS rats (P<0.05);compared to CUPS rats, DAT was upregulated and BDNF was downregulated in NAc of MD rats(p<0.05).(4) in the amygdala(AMy):compared to the control group, DRD1, DRD5, DRD2, DRD3and DRD4protein level were upregulated in AMy of MD rats(p<0.05), DRD5, DRD2, DRD3, DRD4and DAT protein level were upregulated in AMy of CUPS rats(p<0.05); compared to CUPS rats, DRD1was upregulated and DRD4,DAT were downregulated in AMy of MD rats(p<0.05).(5) in the olfactory bulb(OB): compared to control rats, DRD1, DRD5, DRD2, DRD3, DRD4and DAT protein level were upregulated in OB of MD rats(p<0.05), DRD1, DRD2 were upregulated in OB of CUPS rats(p<0.05); No difference in DRD1, DRD5, DRD2, DRD3, DRD4, DAT and BDNF protein level in OB was detected between MD and CUPS rats(p>0.05).(6) the striatum(ST): compared to control rats, DRD5, DRD2, DRD3, DRD4and DAT protein level were upregulated and DRD1was downregulated in ST of MD rats(p<0.05), DRD5, DRD2, DRD3, DAT and BDNF were upregulated and DRDlwas downregulated in ST of CUPS rats(p<0.05); No difference in DRD1, DRD5, DRD2, DRD3, DRD4, DAT and BDNF protein level in ST was detected between MD and CUPS rats(p>0.05).
3.The result of mRNA detection:(1) in ventral tegmental area(VTA): compared to control rats, the mRNA level DRD5, DRD2, DRD3, DRD4, DAT and BDNF were downregulated and DRD1was upregulated in VTA of MD rats(p<0.05), DRD2was upregulated and DRD5, DRD4were downregulated in VTA of CUPS rats(p<0.05); compared to CUPS rats, DRD5,DRD2and BDNF mRNA level were downregulated and DRD1was upregulated in VTA of MD rats(p<0.05).(2) in prefrontal cortex(PFC): compared to control rats, DRD1, DRD5, DRD3, DRD4, DAT and BDNF mRNA level were upregulated in PFC of MD rats(p<0.05), DRD1, DRD5, DAT and BDNF were upregulated and DRD2were downregulated in PFC of CUPS rats(p<0.05); compared to CUPS rats, DRD3, DRD4were upregulated and DRD5,DAT were downregulated in PFC of MD rats(p<0.05).(3) in nucleus accumbens(NAc):compared to control rats, DRD1, DRD5, DRD2, DRD3, DRD4, DAT and BDNF mRNA levels were increased in NAc of MD and CUPS rats(p<0.05); compared to CUPS rats, DAT was upregulated and BDNF was downregulated in NAc of MD rats (p<0.05).(4) in amygdala(AMy):compared to control rats, DRD1, DRD5, DRD2, DRD3and DRD4mRNA levels were increased in AMy of MD rats(p<0.05), DRD5, DRD2, DRD3, DRD4and DAT mRNA levels were upregulated in AMy of CUPS rats(p<0.05); compared to CUPS rats, DRD4, DAT mRNA level were downregulated in AMy of MD rats(p<0.05).(5) in olfactory bulb(OB):compared to control rats, DRD1, DRD5, DRD2, DRD3, DRD4and DAT mRNA level were upregulated in OB of MD rats(p<0.05), DRD1, DRD2were upregulated in OB of CUPS rats(p<0.05); No difference in DRD1, DRD5, DRD2, DRD3, DRD4, DAT and BDNF mRNA level in OB was detected between MD and CUPS rats(p>0.05).(6) in striatum(ST): compared to control rats, DRD5, DRD2, DRD3, DRD4and DAT mRNA level were upregulated and DRD1was downregulated in ST of MD rats(p<0.05), DRD5, DRD2, DRD3, DAT and BDNF increased and DRD1decreased in ST of CUPS rats(p<0.05); No difference in DRD1, DRD5, DRD2, DRD3, DRD4, DAT and BDNF mRNA level in ST was detected between MD and CUPS rats(p>0.05).
4.The result of correlation analysis between behavioral and the biological indices:(1) the number of vertical activity rats performed in open field test is positively correlated with the DRD5, DRD3, DRD4protein level in ventral tegmental area and DRD1protein level in striatum(p<0.05), and was negatively correlated with DRD2、DRD3、DRD4、DAT protein level in striatum and DRD5、DAT protein level in prefrontal cortex(p<0.05);(2)the floating time rats spent in forced swimming test was positively correlated with DRD2、DRD3、DRD4、DAT protein level in amygdala and DRD1、 DRD5、DAT protein level in prefrontal cortex(p<0.05);(3) the sucrose preference rate of rats was positively correlated with DRD5, DRD3, DAT protein level in ventral tegmental area(p<0.05), and was negatively correlated with DRD2、DRD3、DRD4、DAT protein level in nucleus accumbens and DRD1, DRD5, DRD2, DRD3, DRD4, DAT protein level in olfactory bulb(p<0.05).
Conclusion:
1. Dissimilar depressive phenotypes in rats might result from the effect of different chronic psychological stressors.
2. Different chronic psychological stressors might exert dissimilar effects on the D1-like, D2-like dopamine receptor and DAT gene expression in rats'dopaminergic mesocorticolimbic neural pathway.
3. Different depressive-like behaviors might determined by dissimilar abnormality in rats'dopaminergic mesocorticolimbic neural pathway.
4. Different chronic psychological stressors might exert dissimilar effects on neural plasticity in rats' dopaminergic mesocorticolimbic neural pathway.
引文
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